US5093361A - D-2-(6-methoxy-2-naphthyl)-propionic acid and pharmaceutical compositions containing it - Google Patents
D-2-(6-methoxy-2-naphthyl)-propionic acid and pharmaceutical compositions containing it Download PDFInfo
- Publication number
- US5093361A US5093361A US07/485,084 US48508490A US5093361A US 5093361 A US5093361 A US 5093361A US 48508490 A US48508490 A US 48508490A US 5093361 A US5093361 A US 5093361A
- Authority
- US
- United States
- Prior art keywords
- nxtio
- naphthyl
- methoxy
- pharmaceutical compositions
- propionic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
Definitions
- the present invention relates to an optically active isomer of a derivative of d-2-(6-methoxy-2-naphthyl)-propionic acid, namely of the active principle known as Naproxen; the invention relates as well to pharmaceutical compositions containing the said derivative.
- Naproxen is known since a number of years and is included among the substances having anti-inflammatory, analgesic and anti-pyretic activity. Its main therapeutic use is the treatment of rheumatoid arthritis and of other degenerative forms having phlogistic features.
- alpha-mercaptopropionylglycine is a compound known as well, possessing also anti-inflammatory activity besides the mucolytic activity.
- the diastereoisomer of the present invention to the prevailing anti-inflammatory activity which is characteristic both of Naproxen and more remarkably of the derivatives being the subject of the European Patent 124.925, adds a specific analgesic activity which is definitely higher than that the of the corresponding racemic compound.
- the product of the reaction carried out between the acid chloride of d-2-(6-methoxy-2-naphthyl)-propionic acid and (2-mercapto-propionyl)-glycine in the presence of a base is poured in water, then an acidification is carried out with hydrochloric acid and the solid thus precipitated is filtered.
- an acidification is carried out with hydrochloric acid and the solid thus precipitated is filtered.
- repeated fractionated crystallizations, of the racemic one are carried out, using ethyl acetate as the crystallization solvent, until a product having constant melting point (180-1° C.) is obtained.
- each rat received an injection of 0.1 ml of a 1% w/v suspension of carrageenan in sterile 0.9% saline, beneath the plantar aponeurosis of the left hind paw.
- the volume of the paw was measured (in arbitrary units) before and 1.5, 3 and 6 hours after the irritant injection.
- the results are reported in the table 2, from which it can be observed not only that both diastereoisomers administered by oral route induce a significant inhibition of the carrageenan induced oedema, but also that d-l isomer is slightly less active than the d-d isomer.
- the measurement of the paw volume was carried out before the injection and at 0.5, 1 and 2.5 hours after the injection.
- Groups of 10 rats (Wistar-Charles River) were dosed orally with either vehicle (0.5% tragacanth) or test compounds (d-d and d-1 Nxtio) at a costant volume of 10 ml/kg according to the treatment table 1.
- each rat received an intraperitoneal injection of 1.0 ml of 1% solution of acetic acid. They were then placed in individual cages and the number of writhes elicited by each rat in the following 25 minute period was recorded.
- Each rat received an injection of 0.1 ml of a 20% suspension of Brewer's yeast in distilled water beneath the plantar aponeurosis of the left hind paw.
- the pain thresholds of the inflamed and normal hind paws were again measured at 1, 2 and 4 hours after dosing.
- compositions according to the present invention comprise as the active ingredient the (d-d) diastereoisomer together with the standard vehicles and excipients.
- the dosages of active principles shall be still those of the corresponding composition based on Naproxen whereby the therapeutical effect is obviously increased.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Emergency Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The S-[d-2-(6-methoxy-2-naphthyl)-propionyl]d-2-mercaptopropionamidoacetic acid having formula: ##STR1## has improved therapeutic properties not only in comparison with the starting active principle, namely Naproxen, but also with respect to the corresponding racemic derivative, namely the (d,l) compound.
Description
The present invention relates to an optically active isomer of a derivative of d-2-(6-methoxy-2-naphthyl)-propionic acid, namely of the active principle known as Naproxen; the invention relates as well to pharmaceutical compositions containing the said derivative.
Naproxen is known since a number of years and is included among the substances having anti-inflammatory, analgesic and anti-pyretic activity. Its main therapeutic use is the treatment of rheumatoid arthritis and of other degenerative forms having phlogistic features.
In turn, alpha-mercaptopropionylglycine is a compound known as well, possessing also anti-inflammatory activity besides the mucolytic activity.
The derivatives obtained by combining the said two active principles are the object of the European Patent No. 124.925, which thus claims compounds having the following general formula: ##STR2## wherein X is hydrogen or a radical selected from among organic radicals or inorganic radicals, non toxic and pharmaceutically acceptable bases, radicals of basic aminoacids and radicals of basic antibiotics.
The characteristics and properties of the above mentioned compounds in the racemic form, namely the (d,l) form, are given in the specification and in the examples of this European Patent.
It has been now found and is the object of the present invention that the (d,d) diastereoisomer of the compound directly obtained from Naproxen and alpha-mercaptopropionylglycine has surprisingly specific properties which are superior not only to respect with the starting active principle, namely Naproxen, but also with respect to the corresponding (d,l) racemic compound.
This greater activity over Naproxen is mainly seen in the lack of ulcerogenicity which is on the contrary the main drawback of Naproxen as regards the therapeutical use; whereas in comparison with the corresponding racemic compound, the diastereoisomer of the present invention has greater analgesic activity.
Otherwise stated, the diastereoisomer of the present invention to the prevailing anti-inflammatory activity which is characteristic both of Naproxen and more remarkably of the derivatives being the subject of the European Patent 124.925, adds a specific analgesic activity which is definitely higher than that the of the corresponding racemic compound.
It is evident that the therapeutical use of these substances makes the symptomatic activity, namely the analgesic one, of the utmost importance.
As regards the preparation of the diastereoisomer of the present invention, reference is made to the specification and examples of European Patent 124.925, particularly examples 1a and 1b of this patent, which is herein included by reference.
Thus according to the process studied with respect to the present invention, the product of the reaction carried out between the acid chloride of d-2-(6-methoxy-2-naphthyl)-propionic acid and (2-mercapto-propionyl)-glycine in the presence of a base is poured in water, then an acidification is carried out with hydrochloric acid and the solid thus precipitated is filtered. For the separation of the desired (d,d) form; repeated fractionated crystallizations, of the racemic one are carried out, using ethyl acetate as the crystallization solvent, until a product having constant melting point (180-1° C.) is obtained.
The obtained compound has been subjected to elemental analysis with the following results:
Calculated for C19 H21 NO5 S: %C 60.78; %H 5,63; %N 3,73; %S 8,54
Found: %C 61.02; %H 5.59; %N3,71; %S 8.63.
The (d,d) diastereoisomer of the invention is a crystalline solid having [alpha]D 20 +201.01 (C=1, methanol).
It is soluble in ethanol, methanol and acetone, a little soluble in hot ethyl acetate and insoluble in water.
By carrying out the TLC analysis with chloroform: glacial acetic acid: water (85:15:0.5) as the eluant system, a value Rf =0.75 is obtained whereas the (d,l) diastereoisomer has Rf =0.70.
The already mentioned properties of the diastereoisomer according to the invention have been confirmed by the pharmacological tests which are hereinafter shortly reported (the compound of the invention is indicated in abbreviated form has d-d Nxtio whereas the other diastereoisomer is abbreviated as d-1 Nxtio).
As regards the anti-inflammatory activity, the standard tests by means of carrageenan induced oedema and dextran induced oedema were performed whereas for the analgesic activity the writhing test and the Randall-Selitto test have been carried out.
Groups of 8 rats (Wistar-Charles River) have been orally administered with:
(i) vehicle alone (0.5% tragacanth);
(ii) d-d Nxtio at a constant volume of 24 ml/kg in the same vehicle;
(iii) d-l Nxtio at constant volume of 25 ml/kg in the same vehicle. The table 1 hereinafter reports the administration dosages.
TABLE 1 ______________________________________ GROUP TREATMENT VEHICLE DOSE mg/kg p.o. ______________________________________ 1 vehicle -- 2 6.25 3 12.5 4 d-d Nxtio 25.0 5 50.0 6 6.25 7 12.5 8 d-l Nxtio 25.0 9 50.0 ______________________________________
Forty five minutes later each rat received an injection of 0.1 ml of a 1% w/v suspension of carrageenan in sterile 0.9% saline, beneath the plantar aponeurosis of the left hind paw.
The volume of the paw was measured (in arbitrary units) before and 1.5, 3 and 6 hours after the irritant injection. The results are reported in the table 2, from which it can be observed not only that both diastereoisomers administered by oral route induce a significant inhibition of the carrageenan induced oedema, but also that d-l isomer is slightly less active than the d-d isomer.
TABLE 2
__________________________________________________________________________
Effects of oral administration of d-d Nxtio and d-l Nxtio
on a carrageenan-induced oedema in the rat
DOSE
MEAN INCREASE % INHIBITION
mg/Kg
IN PAW VOLUME OF SWELLING
GROUP
TREATMENT
p.o.
1.5 3 6 1.5
3 6
__________________________________________________________________________
1 vehicle 7.9 ± 0.58
12.1 ± 0.52
13.4 ± 0.76
-- -- --
2 d-d Nxtio
6.25
3.7 ± 0.59
5.5 ± 0.57
8.1 ± 0.44
53.2
54.5
39.6
3 12.5
4.7 ± 0.95
8.9 ± 0.90
8.7 ± 1.12
40.5
26.4
35.1
4 25.0
4.3 ± 0.59
8.3 ± 0.95
9.8 ± 0.86
45.6
31.4
26.9
5 50.0
5.0 ± 0.94
8.4 ± 0.76
8.4 ± 0.86
36.7
30.6
37.3
6 d-l Nxtio
6.25
4.1 ± 0.61
6.2 ± 0.62
8.7 ± 0.55
48.1
48.7
35.0
7 12.5
4.9 ± 0.92
9.3 ± 1.10
9.4 ± 1.12
37.9
23.1
29.8
8 25.0
4.6 ± 0.70
8.9 ± 1.2
10.2 ± 0.81
41.7
26.4
23.8
9 50.0
5.6 ± 0.92
8.7 ± 0.8
9.8 ± 0.84
29.1
28.0
26.8
__________________________________________________________________________
This test has been carried out like the preceding one, except that instead of carrageenan 0.1 ml of a 6% suspension w/v of dextran in the same sterile saline solution where injected.
The measurement of the paw volume (in milliliters) was carried out before the injection and at 0.5, 1 and 2.5 hours after the injection.
The results reported in the table 3 confirm the anti-inflammatory activity of both isomers, with a slight superiority of d-d isomer.
TABLE 3
__________________________________________________________________________
Effects of oral administration of d-d Nxtio and d-l Nxtio
on a dextran-induced oedema in the rat
DOSE
MEAN INCREASE % INHIBITION
mg/Kg
IN PAW VOLUME OF SWELLING
GROUP
TREATMENT
p.o.
0.5 1 2.5 0.5
1 2.5
__________________________________________________________________________
1 vehicle 1.09 ± 0.05
1.28 ± 0.04
1.08 ± 0.06
-- -- --
2 d-d Nxtio
6.25
1.03 ± 0.04
1.00 ± 0.03
0.72 ± 0.04
5.5
21.9
33.3
3 12.5
1.12 ± 0.06
1.16 ± 0.04
0.83 ± 0.06
0 9.4
23.2
4 25.0
1.09 ± 0.02
1.11 ± 0.04
0.81 ± 0.03
0 13.3
25.0
5 50.0
1.24 ± 0.05
0.90 ± 0.04
0.73 ± 0.02
0 29.7
32.4
6 d-l Nxtio
6.25
1.04 ± 0.08
1.03 ± 0.07
0.85 ± 0.07
4.6
19.5
21.3
7 12.5
1.11 ± 0.04
1.11 ± 0.08
0.79 ± 0.08
0 13.3
26.8
8 25.0
1.12 ± 0.06
1.14 ± 0.06
0.80 ± 0.06
0 11.0
26.0
9 50.0
1.20 ± 0.05
1.10 ± 0.04
0.9 ± 0.04
0 14.0
16.6
__________________________________________________________________________
Groups of 10 rats (Wistar-Charles River) were dosed orally with either vehicle (0.5% tragacanth) or test compounds (d-d and d-1 Nxtio) at a costant volume of 10 ml/kg according to the treatment table 1.
Forty-five minutes later each rat received an intraperitoneal injection of 1.0 ml of 1% solution of acetic acid. They were then placed in individual cages and the number of writhes elicited by each rat in the following 25 minute period was recorded.
The results of this test are reported in the table 4, from which it can be observed that both diastereoisomers cause a dose dependent inhibition, with a marked superiority of the isomer d-d of the order of 20%.
TABLE 4
__________________________________________________________________________
Analgesic activities of orally administered compounds in
the writhing test - individual animal data
NUMBER OF MEAN
ORAL DOSE
WRITHES/25 MIN FOR ANIMAL No.
WRITHING SCORE
TREATMENT
(mg/Kg) 1 2 3 4 5 6 7 8 9 10
(± s.e.)
__________________________________________________________________________
Vehicle -- 49
54
40
65
43
48
23
65
19
57
46.3 ± 5.24
d-d Nxtio
50 4
10
16
4
24
4
8
6
3
1
8.0 ± 2.36
25 35
7
16
16
5
36
16
36
23
21
21.1 ± 3.81
12.5 42
61
23
25
39
48
38
43
9
7
33.5 ± 5.74
6.25 47
59
33
46
71
23
26
25
24
47
40.1 ± 5.52
d-l Nxtio
50 7
12
10
8
24
7
11
5
9
0
9.3 ± 1.95
25 24
15
32
15
7
28
25
31
20
25
22.2 ± 2.51
12.5 56
65
31
37
44
52
35
41
25
10
39.6 ± 5.03
6.25 48
51
45
39
31
34
46
37
26
72
42.9 ± 4.09
__________________________________________________________________________
Male Wistar rats (70-90 g) were starved 18 hours prior to the commencement of the experiment but water was available ad libitum.
Each rat received an injection of 0.1 ml of a 20% suspension of Brewer's yeast in distilled water beneath the plantar aponeurosis of the left hind paw.
One hour later the pain thresholds of both the inflamed (yeast injected) and normal hind paw were measured using an analgesiometer designed by U. Basile; the animals were then dosed orally with vehicle (0.5% tragacanth) or test compounds at a constant dose volume of 10 ml/kg.
There were 10 rats in each drug-treated group and 20 rats in the vehicle-treated group.
The pain thresholds of the inflamed and normal hind paws were again measured at 1, 2 and 4 hours after dosing.
The results are reported in the table 5 from which it can be observed not only a peak of analgesic effect at two hours from the administration but also the superiority of the (d-d) isomer.
TABLE 5
__________________________________________________________________________
Changes in pain threshold of inflamed and normal paws of rats
receiving oral treatment with d-d Nxtio and d-l Nxtio
MEAN CHANGE IN PAIN THRESHOLD (G ± S.E.)
FROM PRE-DOSE AT POST-DOSE TIME
DOSE 1 HOUR 2 HOURS 4 HOURS
TREAT-
(mg/Kg)
INFLAMED
NORMAL INFLAMED
NORMAL INFLAMED
NORMAL
GROUP MENT p.o. PAW PAW PAW PAW PAW PAW
__________________________________________________________________________
1 vehicle
-- -22.4 ± 15.2
-40.5 ± 17.8
-42.0 ± 15.1
-52.6 ± 18.0
-21.3 ± 15.3
-39.2 ± 13.9
2 d-d Nxtio
6.25 -27.2 ± 30.8
-12.8 ± 17.8
-42.2 ± 21.9
-17.7 ± 18.2
-32.7 ± 15.5
34.1 ± 17.4
3 12.5 32.6 ± 40.1
-13.7 ± 22.9
32.6 ± 41.7
-23.4 ± 18.2
38.9 ± 48.6
10.7 ± 23.7
4 25 53.2 ± 29.9
-1.0 ± 26.0
31.3 ± 35.8
-33.5 ± 24.4
41.9 ± 35.3
18.7 ± 35.9
5 50 48.3 ± 27.9
-1.3 ± 22.9
98.9 ± 38.9
-38.8 ± 18.9
79.4 ± 42.7
25.7 ± 24.3
6 d-l Nxtio
6.25 -21.6 ± 30.9
-14.3 ± 20.0
-38.4 ± 18.9
-24.5 ± 25.3
-23.1 ± 18.4
-10 ± 25.5
7 12.5 25.5 ± 37.3
-15.4 ± 29.6
20.5 ± 38.7
-20.9 ± 25.6
21.2 ± 43.2
-12 ± 15.8
8 25 40.2 ± 31.4
-10.8 ± 27.5
23.2 ± 34.6
-31.5 ± 21.9
29.6 ± 38.1
19 ± 37.7
9 50 42.3 ± 31.6
-1.4 ± 10.3
60.2 ± 45.7
-38.4 ± 22.8
52.1 ± 19.1
18
__________________________________________________________________________
± 22.7
At this point it is worth to noting that the advantages achieved by the present invention must be evaluated as a function of the relevant advancement already achieved with the compounds of the European Patent 124.925 whereby the further improvement which is thus obtained is, in obviously relative terms, a result relevant as well and fully unforeseable.
The pharmaceutical compositions according to the present invention comprise as the active ingredient the (d-d) diastereoisomer together with the standard vehicles and excipients.
In this connection reference is made to the disclosure of European Patent 124.925, which is here incorporated for reference.
The dosages of active principles shall be still those of the corresponding composition based on Naproxen whereby the therapeutical effect is obviously increased.
Claims (2)
1. A method for achieving anti-inflammatory and analgesic effect in a patient in need of such treatment which comprises administering to such patient an effective amount of S-d-2-mercaptopropionamido acetic acid.
2. A pharmaceutical composition useful in achieving anti-inflammatory and analgesic effect in a patient and suitable for administration by oral, topical or rectal route which comprises an effective amount of S-d-2-mercaptopropionamido acetic acid and a pharmaceutically acceptable carrier therefor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT19184A IT1238679B (en) | 1990-01-29 | 1990-01-29 | OPTICALLY ACTIVE DERIVATIVE OF D-2- (6-METHOXY-2-NAFTIL) ACID - PROPIONIC AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT |
| IT19184A/90 | 1990-01-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US5093361A true US5093361A (en) | 1992-03-03 |
Family
ID=11155615
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US07/485,084 Expired - Fee Related US5093361A (en) | 1990-01-29 | 1990-02-26 | D-2-(6-methoxy-2-naphthyl)-propionic acid and pharmaceutical compositions containing it |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5093361A (en) |
| EP (1) | EP0440098B1 (en) |
| KR (1) | KR970011456B1 (en) |
| AT (1) | ATE120731T1 (en) |
| DE (1) | DE69108580T2 (en) |
| ES (1) | ES2071843T3 (en) |
| IT (1) | IT1238679B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223516A (en) * | 1990-03-22 | 1993-06-29 | E. R. Squibb & Sons, Inc. | 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2048640B1 (en) * | 1992-01-30 | 1994-10-01 | Pulitzer Italiana | A METHOD FOR THE PREPARATION OF CETILTRIMETILAMONIO NAPROXENATO. |
| US7163958B2 (en) | 2002-07-03 | 2007-01-16 | Nitromed Inc. | Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use |
| CA2493156A1 (en) | 2002-07-29 | 2004-02-05 | Nitromed, Inc. | Cyclooxygenase-2 selective inhibitors, compositions and methods of use |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0124925B1 (en) * | 1983-04-11 | 1986-11-26 | FARMA RESA SrL | Derivatives of d-2-(6-methoxy-2-naphthyl)-propionic acid having therapeutical activity, process for their preparation and pharmaceutical compositions containing them |
-
1990
- 1990-01-29 IT IT19184A patent/IT1238679B/en active IP Right Grant
- 1990-02-26 US US07/485,084 patent/US5093361A/en not_active Expired - Fee Related
-
1991
- 1991-01-25 AT AT91100947T patent/ATE120731T1/en not_active IP Right Cessation
- 1991-01-25 DE DE69108580T patent/DE69108580T2/en not_active Expired - Fee Related
- 1991-01-25 EP EP91100947A patent/EP0440098B1/en not_active Expired - Lifetime
- 1991-01-25 ES ES91100947T patent/ES2071843T3/en not_active Expired - Lifetime
- 1991-01-29 KR KR1019910001422A patent/KR970011456B1/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0124925B1 (en) * | 1983-04-11 | 1986-11-26 | FARMA RESA SrL | Derivatives of d-2-(6-methoxy-2-naphthyl)-propionic acid having therapeutical activity, process for their preparation and pharmaceutical compositions containing them |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223516A (en) * | 1990-03-22 | 1993-06-29 | E. R. Squibb & Sons, Inc. | 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same |
| US5414013A (en) * | 1990-03-22 | 1995-05-09 | E. R. Squibb & Sons, Inc. | Trifluoromethyl mercaptan and mercaptoacyl derivatives and method of using same |
Also Published As
| Publication number | Publication date |
|---|---|
| KR910014337A (en) | 1991-08-31 |
| EP0440098B1 (en) | 1995-04-05 |
| ATE120731T1 (en) | 1995-04-15 |
| EP0440098A1 (en) | 1991-08-07 |
| KR970011456B1 (en) | 1997-07-11 |
| DE69108580D1 (en) | 1995-05-11 |
| IT9019184A1 (en) | 1991-07-30 |
| ES2071843T3 (en) | 1995-07-01 |
| IT1238679B (en) | 1993-09-01 |
| IT9019184A0 (en) | 1990-01-29 |
| DE69108580T2 (en) | 1996-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI108637B (en) | Process for the preparation of drug-useful trometamine salts of (+) - (S) -2- (3-benzoylphenyl) propanoic acid | |
| US4413141A (en) | 2-(Difluoromethyl)-2,5-diaminopentanoic acid | |
| JPH02104526A (en) | Hypertensive disease treatment composition | |
| US3959356A (en) | Acetylene derivatives of amino acids | |
| US3637660A (en) | Dibenzazepine derivatives | |
| NL8204126A (en) | PROCESS FOR PREPARING A PHARMACEUTICAL PREPARATION WITH A LOCAL ANESTHETIC EFFECT CONTAINING A DIALYLAMINO-2 ', 6'-ACETOXYLIDIDE AND / OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND THE PREPARED PROPERTY OF THESE PREPARED THEREFORE THEREFORE DIALKYLAMINO-2 ', 6'ACETOXYLIDIDS AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS. | |
| FI85469C (en) | Process for the preparation of therapeutically useful 1- (4-hydroxy-3,5-di-tert-butylbenzoyl) homopiperazine derivatives | |
| JPS56145298A (en) | Aminophenyl derivative and physiologically active preparation containing the same | |
| US5093361A (en) | D-2-(6-methoxy-2-naphthyl)-propionic acid and pharmaceutical compositions containing it | |
| US4668504A (en) | Use of substituted propenoates to prevent nephrotoxicity of certain antibiotics | |
| EP0061206A1 (en) | 6-Aminopenicillanic acid esters and their use for producing new ampicillin esters | |
| JPH01149781A (en) | Benzothiazine dioxide derivative | |
| US6066667A (en) | Substituted furanones, compositions and antiarthritic use | |
| US4304785A (en) | Dilignols and dilignol-type compounds | |
| FI73970C (en) | FOERFARANDE FOER FRAMSTAELLNING AV PHARMACEUTISKT AKTIVA 2-AMINO-3- (HALOBENSOYL) -METHYL-PHENYL ETHYL OCH ESTRAR OCH SALTER DAERAV. | |
| EP0177356A2 (en) | Method for treatment of antidiuresis | |
| US20030100516A1 (en) | Analgesic agent | |
| US3928621A (en) | Antiinflammatory 2-(2-aminoalkylamino)-1,2-diphenylethanols | |
| EP0045473B1 (en) | A pharmaceutical composition containing a benzofuran-carboxamide derivative as the active ingredient | |
| FR2518537A1 (en) | NOVEL DERIVATIVES OF PHENYLACETIC ACID, THEIR PREPARATION AND COMPOSITIONS CONTAINING SAME | |
| FI105919B (en) | Process for the preparation of pharmaceutically acceptable acid addition salts of the 2- (1-pyrrolidinyl) ethyl ester of (+) - 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid | |
| SU1447283A3 (en) | Method of producing condensed derivatives of as-triazine | |
| US4562205A (en) | Derivatives of 2-aminoacetic acid | |
| US4014921A (en) | O-Acetoxy benzoate ester of 2(p-acetamido-phenyloxy)ethyl alcohol | |
| US3448141A (en) | Unsymmetrical derivatives of djenkolic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: FARMA RESA S.R.1., ITALY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:REINER, VALENTINA;SARDA, CATERINA;REEL/FRAME:005239/0899 Effective date: 19900220 |
|
| FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
| FPAY | Fee payment |
Year of fee payment: 4 |
|
| REMI | Maintenance fee reminder mailed | ||
| LAPS | Lapse for failure to pay maintenance fees | ||
| FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20000303 |
|
| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |